Dykxhoorn Derek M, Da Fonseca Ferreira Andrea, Gomez Karenn, Shi Jianjun, Zhu Shoukang, Zhang Lukun, Wang Huilan, Wei Jianqin, Zhang Qianhuan, Macon Conrad J, Hare Joshua M, Marzouka George R, Wang Liyong, Dong Chunming
John T. Macdonald Foundation Department of Human Genetics and, the John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Int J Mol Sci. 2025 Apr 30;26(9):4259. doi: 10.3390/ijms26094259.
EPCs play important roles in the maintenance of vascular repair and health. Aging is associated with both reduced numbers and functional impairment of EPCs, leading to diminished angiogenic capacity, impaired cardiac repair, and increased risk for cardiovascular disease (CVD). The molecular mechanisms that govern EPC function in cardiovascular health are not fully understood, but there is increasing evidence that microRNAs (miRNAs) play key roles in modulating EPC functionality, endothelial homeostasis, and vascular repair. We aimed to determine how aging alters endothelial progenitor (EPC) health and functionality by altering key miRNA-mRNA pathways. To identify key miRNA-mRNA pathways contributing to diminished EPC functionality associated with aging, microRNA and mRNA profiling were conducted in EPCs from young and aged C57BL/6 mice. We identified a complex aging-associated regulatory network involving two miRNAs-miR-29c-3p and -126a-that acted in tandem to impair vascular endothelial growth factor signaling through targeting Klf2 and Spred1, respectively. The modulation of components of the miR-29c-3p-Klf2-miR-126a-Spred-1-Vegf signaling pathway altered EPC self-renewal capacity, vascular tube formation, and migration in vitro, as well as cardiac repair in vivo. The miR-29c-3p-Klf2-miR-126a-Spred1-Vegf signaling axis plays a critical role in regulating the aging-associated deficits in EPC-mediated vascular repair and CVD risk.
内皮祖细胞（EPCs）在维持血管修复和健康方面发挥着重要作用。衰老与EPCs数量减少和功能受损相关，导致血管生成能力下降、心脏修复受损以及心血管疾病（CVD）风险增加。虽然调控EPCs在心血管健康中功能的分子机制尚未完全明确，但越来越多的证据表明，微小RNA（miRNAs）在调节EPCs功能、内皮细胞稳态和血管修复中起关键作用。我们旨在确定衰老如何通过改变关键的miRNA-信使核糖核酸（mRNA）通路来改变内皮祖细胞（EPC）的健康和功能。为了确定导致与衰老相关的EPCs功能下降的关键miRNA-mRNA通路，我们对年轻和老年C57BL/6小鼠的EPCs进行了微小RNA和mRNA谱分析。我们确定了一个复杂的与衰老相关的调控网络，该网络涉及两种微小RNA——miR-29c-3p和-126a，它们分别通过靶向Klf2和Spred1协同作用，损害血管内皮生长因子信号传导。对miR-29c-3p-Klf2-miR-126a-Spred-1-Vegf信号通路成分的调节改变了EPCs的自我更新能力、体外血管管形成和迁移，以及体内心脏修复。miR-29c-3p-Klf2-miR-126a-Spred1-Vegf信号轴在调节与衰老相关的EPC介导的血管修复缺陷和CVD风险中起关键作用。
